Hyaluronan, also called hyaluronic acid or hyaluronate or abbreviated HA, is a naturally occurring anionic, non-sulfated glycosaminoglycan whose repeating disaccharide is composed of β-(1,3)-D-glucuronic acid (left-hand portion below)(glucuronic acid) (GlcUA) and β-(1,4)-N-acetyl-D-glucosamine (right-hand portion below)(N-acetyl glucosamine)(GlcNAc).

HA is found in numerous places in humans and animals, including the vitreous humor of the eyes, the skin, the extracellular matrices of virtually all tissues, and synovial fluids of articular joints (e.g., the knee). The presence of HA is crucial during embryonic development for proper organogenesis and for scar-free healing in the fetus. The molecular weight (MW) of naturally occurring HA widely varies depending on its location and can be from about 0.200 to 10 MDa (million Daltons). The half-life of HA also widely varies depending on its location and can last from hours in synovial fluid to weeks in the extracellular matrix.
HA and its many chemical derivatives have multiple commercial uses that are typically dependent upon the MW of the HA. High MW HA, e.g., >0.5 MDa, is used for wound healing after cataract surgery (e.g., via ophthalmic injections) and as a visco-supplement to provide cushioning and lubrication and to reduce the pain of osteoarthritis in knees or other joints (e.g., via intra-articular injections). Other uses of HA and its chemical derivatives include wound healing in general, adhesion prevention after surgery, cell engineering, and in cosmetics (e.g., skin moisturizers).
While the viscoelastic properties of high MW HA provide lubrication to joints and protect sensitive tissues during and after surgery, these properties are lost when HA is degraded in vivo (e.g., enzyme or radical degradation). Lower MW HA can actually be inflammatory or angiogenic instead of anti-inflammatory or anti-angiogenic. The degradation of high MW and also lower MW HA results from naturally occurring hyaluronidases. In addition, substantial degradation also results from oxidation, mostly likely through hydroxyl radicals and a variety of reactive oxygen species (ROS) that can be produced as part of the pathology of inflammatory diseases. This has been reviewed in, for example, by G. Kogan, L. Soltes, R. Stern, and R. Mendichi, “Hyaluronic acid: a biopolymer with versatile physico-chemical and biological properties: In: Handbook of Polymer Research: Monomers, Oligomers . . . (R. A. Pethrick et al, Eds.), pp 393-439 (2007) Nova Science Publishers.)
Numerous solutions have been devised to slow the in vivo degradation of HA and to modify its chemical, physical, and biological properties. These solutions typically involve chemical modification of the HA, including for example crosslinking by chemical or photochemical means. Examples of crosslinking agents include thiols (with thiols and electrophiles such as acrylates), methacrylates, tyramines, formaldehyde (Hylan-A), divinyl sulfone (Hylan-B), biscarbodiimides (Monovisc), and cinnamate dimers (Gel-One). Other solutions include modifying HA with a large group such as a polypeptide to induce cell attachment or self-assembly into a hydrogel. Unfortunately, chemical modifications often times lead to side effects and foreign body reactions not observed with unmodified HA, which has naturally low immunogenicity and low toxicity. The chemistry and biology of HA, the medical uses of HA, and the scope of chemical modifications employed in research and medical products are the subject of recent reviews, including: J. W. Kuo and G. D. Prestwich, “Chapter 73. Hyaluronic Acid” in Materials of Biological Origin—Materials Analysis and Implant Uses, Comprehensive Biomaterials, Vol. 2 (eds. P. Ducheyne, K. Healy, D. Hutmacher, J. Kirkpatrick), Elsevier pp. 239-259 (2011) and J. Burdick, G. D. Prestwich, “Hyaluronic Acid Hydrogels for Biomedical Applications”, Advanced Materials 23, H41-H56 (2011).
In view of its numerous uses and its known susceptibility to degradation, there is a need for improved HA and HA-containing compositions.